Individual Members of the Microbiota Disproportionately Modulate Host Innate Immune Responses

Abstract

Summary Predicting host health status based on microbial community structure is a major goal of microbiome research. An implicit assumption of microbiome profiling for diagnostic purposes is that the proportional representation of different taxa determine host phenotypes. To test this assumption, we colonized gnotobiotic zebrafish with zebrafish-derived bacterial isolates and measured bacterial abundance and host neutrophil responses. Surprisingly, combinations of bacteria elicited immune responses that do not reflect the numerically dominant species. These data are consistent with a quantitative model in which the host responses to commensal species are additive, but where various species have different per capita immunostimulatory effects. For example, one species has a high per capita immunosuppression that is mediated through a potent secreted factor. We conclude that the proportional representation of bacteria in a community does not necessarily predict its functional capacities; however, characterizing specific properties of individual species offers predictive insights into multi-species community function.

Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts

“…Consistent with the keystone-pathogen concept, a recent study on the intestinal innate immune response of gnotobiotic zebrafish showed that combinations of distinct bacterial species induce immune responses that do not reflect the numerically dominant species [43]. Rather, different species exert different ‘per capita’ immunostimulatory effects, suggesting that knowledge of specific properties of individual species may provide predictive insights into the function of multi-species communities [43].…”

“…Rather, different species exert different ‘per capita’ immunostimulatory effects, suggesting that knowledge of specific properties of individual species may provide predictive insights into the function of multi-species communities [43]. Moreover, the fact that minor members can exert dominant effects challenges the Occam’s razor interpretation (which is inherent in compositional analyses) that the relative abundances of different taxa or species can have predictive value for pathology.…”

“…However, as noted above, B. thetaiotaomicron can also upregulate virulence gene expression in EHEC [32], underscoring the contextual nature of classifying bacterial disease potential. In a gnotobiotic zebrafish model, low-abundance Shewanella (probiotic species used in aquaculture) acts as a keystone stabilizer by exerting a disproportionately large effect on intestinal neutrophil influx [43]. Specifically, Shewanella secretes an anti-inflammatory factor that overrides the pro-inflammatory effects of high-abundance species of the community [43].…”

High-dimensional microbiome interactions shape host fitness

“…17,18 Each microbial response may impact the host, and host feedbacks can mitigate or exacerbate changes in the microbial community. 19 However, vignette examples may be misleading, as the true complexity of a gut microbiome has never been exhaustively quantified. Thus, it remains an outstanding challenge to reverse engineer the interaction networks that characterize community microbiome-host effects relative to host interactions with a single bacterial species.…”

The gut microbiota and immune checkpoint inhibitors

“…33 Although apparently contradictory, the diversity of the gut microbiome could include some species of bacteria as suppressive while others could function to stimulate an immune inflammatory response. 34 Rutkowski and colleagues did not find a significant difference in the quantity of PD-1 between Tlr5-/- and wild-type mice models, however, it could be of further interest to measure responses to anti-CTLA-4 Ab. Even more intriguingly, the functional role of TLR-5 immunosuppressive bacteria might be useful for research regarding the efficacy of immunosuppressive drugs such as anti-CD3 mAb, or teplizumab, supported by preliminary investigations focusing on the synergistic functionality between gut commensal bacteria and immunosuppressive drugs.…”